WO2014020222A1

WO2014020222A1 - Solid pharmaceutical composition of cation exchange resin

Info

Publication number: WO2014020222A1
Application number: PCT/ES2013/070565
Authority: WO
Inventors: Jose Luis Fabregas Vidal; Joaquin GOMEZ TOMAS; Nuria RUIZ XIVILLE
Original assignee: Laboratorios Rubio, S.A.
Priority date: 2012-08-03
Filing date: 2013-07-31
Publication date: 2014-02-06
Also published as: US9474714B2; EP2881106A1; EP2881106B1; ES2441468A1; ES2441468B1; ES2734557T3; US20150174065A1

Abstract

The present invention relates to a solid pharmaceutical composition of cation exchange resin that makes it possible to prepare a stable resin suspension in an aqueous medium, and to re-suspend the resin easily if sedimentation occurs. The composition comprises hydroxypropylmethylcellulose and pregelatinized starch as functional excipients. The invention also relates to a solid oral administration form comprising the composition, to the use of the same for preparing solid oral administration forms, and to the composition for use in the treatment of hyperkalemia.

Description

D E S C R I P C I Ó N

"SOLID PHARMACEUTICAL COMPOSITION OF EXCHANGE RESIN

CATIÓNICO "

Technical field

The present invention is framed within the scope of the development of compositions for the treatment of hyperkalemia comprising a cation exchange resin.

Prior art

Potassium has multiple functions in the body: it regulates the activity of smooth tissue muscles, heart muscles and skeletal muscles, intervenes in enzymatic reactions involved in digestion and other metabolic processes of the body, and plays a role in homeostasis , the mechanism used by the body to maintain a balance between the many electrical and chemical processes of the body.

Almost all of the potassium in the body is found intracellularly, while only about 2% is found in extracellular fluids. Blood tests reveal extracellular potassium levels and are not indicative of the amount of intracellular potassium. The movement of potassium inside or outside the cells can change the plasma level of potassium, although there is no change in the total amount of potassium in the body.

Hyperkalemia or hyperkalemia is a hydroelectrolytic disorder that is defined when the elevated plasma potassium level is above approximately 5.5 mmol / l.

The causes of hyperkalemia may be due to an increase in potassium intake, a redistribution thereof, or a decrease in renal excretion. Symptoms associated with hyperkalemia are generally nonspecific and include general malaise, palpitations and muscle weakness. Very high levels of potassium constitute a medical emergency, since there is a risk of cardiac arrhythmias. Hyperkalemia treatments include, for example, therapies with calcium gluconate, glucose-insulin, sodium bicarbonate, dialysis, or cation exchange resins.

Therapy with a cation exchange resin is the most recommended for the daily control of potassium in a situation of hyperkalemia due to chronic renal failure. Such therapy involves the removal of potassium from the body by replacing in the digestive tract potassium ions with calcium or sodium ions from a cation exchange resin, usually a polystyrene sulfonate resin.

In Europe, the recommended dose is 15 g of calcium polystyrene sulfonate up to three or four times a day. In the US, the product marketed is sodium polystyrene sulfonate administered according to the same dosage. However, in Japan and Korea, the accepted dose is 5 g of resin up to three times a day.

Usually, the polystyrene sulfonate resin is administered orally as a suspension in water. It should be borne in mind that the resin is a practically water insoluble powder, which has a tendency to settle rapidly. In addition, given that due to its dose for the treatment to be effective the resin must be taken in a large amount, during the ingestion of the same the patient has a prolonged unpleasant sensation in the oral cavity. This translates into a low degree of compliance with the indications of the prescription in regard to taking the medication according to the recommended dosage schedule.

Therefore, the problem of hyperkalemia therapy with cation exchange resins lies mainly in the difficulty of preparing a sufficiently stable suspension thereof, the difficulty of resuspending the resin in the case of sediment formation, and poor palatability. due to repeated oral ingestion of a large dose of resin throughout the day (every 8 hours).

Different approaches have been described in the prior art to address one or more of the aforementioned problems.

European patent application EP-A-0564154 describes formulations in the form of stable aqueous suspensions, which contain an ion exchange resin (which incorporates a pharmaceutical substance resin-bound bound thereof), a thickening agent to increase viscosity, and an amino acid that acts as a dispersion stabilizer.

US-A-2007/0248564 describes stable aqueous suspensions of sodium polystyrene sulphonate, ready to use and intended for the treatment of hyperkalemia, comprising magnesium aluminum silicate as suspending agent and which are free of sorbitol .

International patent application WO-A-2010/132662 refers to powdery compositions that comprise at least 40% of a potassium-picking active ingredient and that are suitable for the treatment of hyperkalemia. In particular, compositions are described which contain an active substance that captures potassium, a suspending agent, a sliding agent, sorbitol and water.

European gel application EP-A-1004310 describes gelled aqueous compositions comprising an ion exchange resin and one or more gelling agents.

Gelled compositions are also described in European patent application EP-A-1031345. Said compositions comprise at least one gelling agent, water and a polystyrene sulfonate resin, having an average particle size between 5 and 100 μηι. The compositions must be kept in refrigerated conditions to obtain gel consistency, which makes the production process difficult. This document also describes the improvement in compliance that has been observed in some Japanese hospitals where the resin is administered in the form of gelatin preparation. However, it is also indicated that said preparations have poor palatability.

European patent application EP-A-0976408 is directed to formulations for the treatment of hyperkalemia containing cation exchange resins as active ingredient, sodium carboxymethyl cellulose as gelling agent and hydroxypropyl cellulose as binding agent. Said formulations are in the form of powder or granules that must be taken after suspending them in water. This document highlights the problems of poor palatability of this type of drugs, and it is intended to prepare a new formulation that is easily dispersible in water, that said dispersion does not form aggregates after preparation and can easily be resuspended if a precipitate forms. The assessment of the palatability of said compositions is carried out by suspending 3.7 g, corresponding to 3.3 g of cation exchange resin, in 33 ml of water, which correspond to the dosage commonly used in Japan. These compositions have the disadvantage of high viscosity when used in European conditions (15 g of resin in 100 ml of water) and containing sodium ions, which is not generally advisable, nor for patients with renal insufficiency.

In the North American market there is also the SPS ^® Suspension product, which is a suspension of the sodium polystyrene sulfonate resin in sorbitol, a high density liquid that is used to stabilize the suspension. However, in Chaudhury, et al., Am. J. Kidney Dis., 1997, 30 (1), 120-122, it has been described that concomitant use of said resin and sorbitol can cause intestinal necrosis.

None of the proposed solutions satisfactorily solves the problem of oral administration of ion exchange resins for the treatment of hyperkalemia.

The need therefore remains to have a composition for oral administration of ion exchange resins that, once constituted, allows the formation of a stable suspension thereof, an easy resuspension in the case of the formation of a sediment, a palatability improved and absence of sodium ions, in order to achieve compliance by the patient of the prescribed dosage regimen.

Summary of the Invention

The object of the present invention is a solid pharmaceutical composition comprising a cation exchange resin as an active ingredient.

Said composition is also part of the object of the invention for use in the treatment of hyperkalemia.

The use of said composition to prepare solid forms of a cation exchange resin for oral administration is also part of the object of the invention. A solid form for oral administration comprising said composition is also part of the object of the invention. Description of the figures

Figure 1

Figure 1 shows the viscosity of aqueous suspensions obtained by incorporating a unit dose of the compositions prepared in Example 1 and in Comparative Examples 1 and 2 in 100 ml of water. In ordinates the viscosity expressed in mPa.s is represented and in abscissa the time elapsed since the addition of water to the sample expressed in minutes.

Figure 2

Figure 2 depicts the viscosity of aqueous suspensions obtained by incorporating a unit dose of the compositions prepared in Example 1 and in Comparative Examples 3 to 5 in 100 ml of water. In ordinates the viscosity expressed in mPa.s is represented and in abscissa the time expressed in minutes.

Figure 3

Figure 3 shows the viscosity of aqueous suspensions obtained by incorporating a unit dose of the compositions prepared in Examples 1 and 2, and in Comparative Examples 3 to 5 in 100 ml of water after a one hour rest. In ordinates the viscosity expressed in mPa.s is represented and in abscissa the time expressed in minutes. A maximum viscosity value can be identified in the figure, which gives an indication of the starting force required to start the viscometer spindle.

Figure 4

Figure 4 shows the viscosity of aqueous suspensions obtained by incorporating a unit dose of the compositions prepared in Examples 1 and 2, and in Comparative Examples 3 to 5 in 100 ml of water after a one hour rest. In ordinates the normalized viscosity expressed in mPa.s / cm is represented and in abscissa the time expressed in minutes. The normalized viscosity is the result of dividing the viscosity by the height of the resin sediment. Normalization is carried out to eliminate the influence of said height on the force necessary to start the viscometer spindle.

Detailed description of the invention

A subject of the invention is a solid pharmaceutical composition comprising a cation exchange resin, hydroxypropyl methylcellulose and pregelatinized starch.

The authors of the present invention have developed a solid pharmaceutical composition comprising a cation exchange resin as an active ingredient that, surprisingly, allows the preparation of a stable suspension of the resin, which is easily resuspended in the case of the formation of a sediment, and which has improved palatability and is substantially free of sodium ions.

Said composition facilitates a greater degree of compliance on the part of the patient who is subject to chronic therapy by cation exchange resins.

In a particularly preferred embodiment the solid pharmaceutical composition consists essentially of a cation exchange resin, hydroxypropyl methylcellulose and pregelatinized starch.

In the context of the invention, the expression "consists essentially of" limits the scope of the claim to the materials contained therein and those that do not materially affect the basic characteristics of the composition of the invention. In this sense it is understood that the composition may comprise other excipients such as, for example, sweetening agents, flavoring agents, or coloring agents.

Flavoring agents and sweetening agents can be incorporated into the composition to increase the taste and / or mask any unpleasant flavors.

In a preferred embodiment, the solid pharmaceutical composition further comprises a flavoring agent and, optionally, a sweetening system.

The sweetener system may be formed by one or more sweetening agents. The flavoring agent can be selected from the group which includes, for example, aroma of various fruits, pineapple, strawberry, raspberry, banana, banana, orange, lemon, lime, apricot, peach, cherry, licorice, mint, vanilla, chocolate, coffee , and combinations thereof.

The content of flavoring agent in the composition of the invention may be comprised between 0.1% and 1% by weight over the total weight of the composition, and preferably between 0.25% and 0.75%.

The sweetening agent constituting the sweetener system may be selected from the group formed, for example, fructose, xylitol, sucrose, sucralose, glucose, maltose, steviose, mannitol, thaumatine, neohesperidinadihydrochalcone (Neo-DHC), aspartame, saccharin, cyclamate, and combinations thereof.

The content of the sweetener system in the composition of the invention may be between 0.05% and 0.5% by weight over the total weight of the composition, and preferably between 0.1% and 0.2% .

Cation exchange resin

In the composition of the invention the active ingredient is a cation exchange resin.

In the context of the invention the cation exchange resin is preferably selected from the group consisting of calcium polystyrene sulfonate and sodium polystyrene sulfonate.

In a preferred embodiment the resin is sodium polystyrene sulfonate.

In another preferred embodiment the resin is calcium polystyrene sulfonate.

Sodium or calcium polystyrene sulfonate is a polymer, whose basic unit is styrene (vinylbenzene) sulfonated in the form of sodium salt or calcium salt. It is generally crosslinked with a difunctional monomer such as divinylbenzene. Said polymer has the functionality of acting as a cation exchange resin, so that, as it circulates through the intestine after oral administration, calcium or sodium ions are partially replaced by potassium ions with the consequent release of calcium ions or sodium.

Cation exchange resins are commercially available, for example, under the name Amberlite ^® (Cario Erba). The polymers described in the international patent application WO-A-2010/132662 can also be used as cation exchange resin.

Typically, in the composition of the invention the cation exchange resin content is between 95.0% and 99.8% by weight with respect to the total weight of the composition, preferably between 95.5% and 98 , 5%%, more preferably between 96.0% and 97.5%, and even more preferably between 96.5% and 97.0%.

Hydroxypropyl methylcellulose

Hydroxypropyl methylcellulose (hereinafter HPMC) is a cellulose that is partially methylated and partially 2-hydroxypropylated in the hydroxyl groups that constitute it.

HPMC is available in various grades that vary in viscosity and extent of substitution. Generally the various grades are distinguished from each other by the apparent viscosity expressed in mPa.s of an aqueous solution of HPMC at 2% by weight and determined at 20 ^e C.

The specifications of the different types of HPMC are described, for example, in the R.C. Rowe et al., Handbook or Pharmaceutical Excipients, A-edition, Pharmaceutical Press, London, 2003 [ISBN: 0-85369-472-9].

HPMC is an excipient commonly used in pharmaceutical compositions for oral and topical administration. In the preparation of tablets, it is used as a binding agent, and also to modulate the rate of release of the active substance. In liquid compositions it can be used as a viscosifying agent and suspending agent to inhibit sediment formation.

HPMC is commercially available through various companies under the name Methocel ^® (Dow), Benecel ^® (Ashland), Metolose ^® (Shin-Etsu), Pharmacoat ^® (Shin-Etsu), Tylopur ^® (Shin-Etsu), or Spectracel ^® (Sensient).

In the composition of the invention, preferably HPMC selected from types 2208 (USP) having an apparent viscosity between 100-140,000 cps is used, more preferably between 80,000-120,000 cps, and even more preferably an apparent viscosity of about 100,000 cps.

Usually, in the composition of the invention, the content of HPMC is comprised between 0.1% and 2.5% by weight with respect to the total weight of the composition, preferably between 0.75% and 2, 25%, and more preferably between 1.25% and 2.0%, and even more preferably between 1.4% and 1.8%.

Pregelatinized starch

Pregelatinized starch is a starch that has been treated by chemical or mechanical processes to partially or completely break the starch granules and transform it into fluid and compressible starch. Starch can be obtained from corn, rice or potato.

Typically, pregelatinized starch comprises 5% free amylose, 15% free amylopectin, and 80% unmodified starch.

The specifications of pregelatinized starch are described, for example, in the R.C. Rowe et al., Already cited.

Pregelatinized starch is usually used as a binding agent in the preparation of tablets in percentages greater than 5% over the total weight of the composition, up to 20%.

Pregelatinized starch is commercially available through various companies under the name Lycatab ^® (Roquette), Merigel ^® (Tate & Lyle), National ^® (National Starch), Unipure ^® (National Starch), PharmaGel ^® (Staple Food Products), Prejel ^® (DFE Pharma), Sepistab ^® (Seppic), or Spress ^® (GPC).

Usually, in the composition of the invention, the prelegatinized starch content is comprised between 0.1% and 2.5% by weight with respect to the total weight of the composition, preferably between 0.75% and 2.25 %, and more preferably between 1.25% and 2.0%, and even more preferably between 1.4% and 1.8%.

In the composition of the invention the sum of the percentages by weight of the components is adjusted to 100%, and they refer to the percentage by weight over the total weight of the composition. In a preferred embodiment the composition of the invention comprises between 95% and 97.5% by weight of cation exchange resin, between 1.25% and 2.5% by weight of HPMC, and between 1, 25% and 2.5% by weight of pregelatinized starch.

In a more preferred embodiment the composition of the invention comprises between 95% and 97.5% by weight of cation exchange resin, between 1.25% and 2.5% by weight of HPMC, between 1, 25% and 2.5% by weight of pregelatinized starch, between 0.1% and 1% by weight of a flavoring agent and between 0.05% and 0.5% by weight of a sweetener system.

Surprisingly, the incorporation of the combination of pregelatinized starch and HPMC into a solid composition of a cation exchange resin allows the preparation of a suspension of the resin in an aqueous vehicle that is substantially stable for normal administration, which is easily resuspended in the case of the formation of a sediment, which has an improved palatability and which is also substantially free of sodium ions.

Said composition is appropriate for the treatment of hyperkalemia and with it a greater degree of compliance is achieved by the patient due to its good sensory characteristics.

Solid forms for oral administration.

The use of the composition of the invention to prepare solid forms of a cation exchange resin for oral administration is part of the invention.

Also part of the object of the invention is a solid form for oral administration comprising a therapeutically effective amount of the composition of the invention.

Given the characteristics of the medicine and the amount of it that must be taken to be effective, solid forms for oral administration are presented as a unit dose or in a bulk container for unit dosage at the time of administration to the patient. In a preferred embodiment the solid form for oral administration is a unit dose, and more preferably the unit dose is contained in an overdose-shaped container.

The package can be, for example, satin paper, or a heat-sealed aluminum and plastic laminate. Preferably the envelope is formed by an aluminum and plastic laminate, since it offers superior protective quality and is capable of being used in high speed packaging machines.

In a preferred embodiment, the unit dose comprises an amount of cation exchange resin comprised between 5 g and 20 g, preferably between 10 g and 18 g, more preferably between 14 g and 16 g, and even more preferably 15 g; an amount of HPMC comprised between 0.08 g and 0.33 g, preferably between 0.17 g and 0.30, more preferably between 0.23 g and 0.27 g, and more preferably between 0.24 g and 0.26 g; and an amount of pregelatinized starch comprised between 0.08 g and 0.33 g, preferably between 0.17 g and 0.30, more preferably between 0.23 g and 0.27 g, and more preferably between 0.24 g and 0.26 g.

In a more preferred embodiment, the unit dose comprises 15 g of cation exchange resin, 0.25 g of HPMC and 0.25 g of pregelatinized starch.

In an even more preferred embodiment, the unit dose comprises 15 g of cation exchange resin, 0.25 g of HPMC, 0.25 g of pregelatinized starch, 0.10 g of flavoring agent, preferably banana flavor, and a combination of 0.02 g of sucralose, and 0.01 g of Neo-DHC as a sweetener system.

Said unit dose is administered by suspending the content thereof in an amount of water comprised between 50 ml and 150 ml, preferably between 70 ml and 120 ml, more preferably between 80 ml and 10 ml, and even more preferably 100 ml. .

As already mentioned above, the composition of the invention can also be presented in an appropriate bulk container, such as, for example, a wide-mouth glass or plastic canister, accompanied by a spoon adapted to facilitate the correct dosage of the required amount of the composition of the invention. Rheological tests

In one test, aqueous suspensions were prepared from unit doses of a composition of the invention and of the compositions prepared following the kneading / granulation process in aqueous route described in examples 1 and 2 of patent application EP-A-0976408 , as described in the Examples section.

In Figure 1 it can be seen that the compositions described in the state of the art have a viscosity much higher than that considered convenient for oral administration, and significantly higher than the viscosity of the composition of the invention, which has a viscosity below or close to 100 mPa.s, and that is appropriate for oral administration.

In another test, aqueous suspensions were prepared from unit doses of the composition of the invention and from compositions that did not contain HPMC, or pregelatinized starch, or contained only HPMC or pregelatinized starch, as described in the Examples section.

When analyzing the viscosity values in the initial instants of the suspension preparation, it can be seen in Figure 2 that, when the formulation does not include HPMC, the presence of pregelatinized starch in the formulation has virtually no influence on the viscosity at 1 minute, while said starch exerts a significant effect in the presence of HPMC. This results in a synergistic effect of the combination of pregelatinized starch and HPMC on the viscosity of the suspension in the initial instants and at least up to 15 minutes.

It is also observed in the same Figure 2 that in the compositions that do not comprise HPMC a massive sedimentation of the cation exchange resin appears, while the composition of the invention has an initial viscosity of approximately 80 mPa.s which is kept substantially stable during a time not less than 15 minutes, and substantially constant up to 40 minutes. It is also noted that the viscosity recorded for the composition containing only hydroxypropyl methylcellulose as an excipient, is significantly lower than that obtained with the composition of the invention. Therefore, it can be concluded that, surprisingly, the combination of HPMC and pregelatinized starch of the composition of the invention allows the preparation of a suspension of the cation exchange resin virtually instantaneously, and stable for at least 15 minutes.

Resuspension Tests

Aqueous suspensions were prepared from unit doses of compositions of the invention (Examples 1 and 2), and of compositions containing only HPMC or pregelatinized starch, and which did not contain HPMC, or pregelatinized starch (Comparative Examples 3, 4 and 5) .

The suspensions were prepared by dispersing the compositions in a given amount of water, in proportion to a unit dose per 100 ml of water, kept under stirring for a time of 2 minutes, and then kept at rest for 1 hour.

Next, the viscosity of the suspension was determined by a viscometer, to identify the exact point of rupture of the solids sediment, which is related to the force necessary to initiate the resuspension of the sediment, that is, an indication of the necessary starting force to start the viscometer spindle.

It was observed (Figure 3) that the combination of pregelatinized starch and HPMC of the composition of the invention leads to a viscosity at the breaking point significantly lower than that observed when only one of the excipients is used, or when no excipient is used . The same effect can be seen in Figure 4, in which the normalized viscosity expressed in mPa.s / cm has been represented, which is the result of dividing the viscosity by the height of the resin sediment.

Accordingly, it can be concluded that, surprisingly, the combination of HPMC and pregelatinized starch of the composition of the invention leads to the formation of cation exchange resin suspensions with significant resuspension capacity.

Sensory test A suspension prepared with 15.63 g of a composition of the invention according to Example 5 in 100 ml of water was evaluated by a panel composed of 30 people in relation to its organoleptic acceptability and preference will in comparison with a composition represented by that of Comparative Example 5, flavored with the presence of 0.04 g of vanilla essence per unit dose, ie a cation exchange resin composition free of functional excipients (HPMC and pregelatinized starch).

The characteristics of the composition represented by Example 5 were positively assessed by the panelists obtaining a good grade. Thus, due to the concept of acceptance of the organoleptic properties of the composition represented by Example 5, they were evaluated by the panel as 42% higher than those of the composition represented by Comparative Example 5 flavored as indicated, and 87% of the panel declared its preference for the composition of Example 5, again in comparison with the result of Comparative Example 5 flavored.

In a second test, suspensions prepared with a unit dose (15 g of resin in 100 ml of water) of the compositions of examples 1 and 2 of patent application EP-A-0976408 (Comparative Examples 1 and 2), They had a high viscosity. This characteristic contributed to the negative evaluation of the same ones made by the panelists regarding the ease of ingesting them. In addition, a significant part of the medication remained in the glass, requiring the use of an additional amount of water to ingest it, which increases the daily intake of liquid, mostly in the daily administration schedule of every 8 hours, and is inappropriate for patients with renal insufficiency.

Therefore, it can be concluded that the compositions of the invention have a good sensory evaluation by patients, which may contribute to a greater degree of compliance with the prescribed dosage regimen.

The following examples are set forth in order to provide the skilled person with a sufficiently clear and complete explanation of the present invention, but should not be considered as limitations on the essential aspects of the object thereof, as they have been exposed in the previous sections of this description. Examples

Comparative Example 1: Composition Preparation of Example 1 of Patent Application EP-A-0976408

Following the aqueous kneading / granulation process described in Example 1 of patent application EP-A-0976408, a composition containing 15.00 g of calcium polystyrene sulphonate resin and 1.5 g of per unit dose was prepared sodium carboxymethyl cellulose (1900 mPa.s at 2%). Comparative Example 2: Preparation of the composition of Example 2 of patent application EP-A-0976408

Following the aqueous kneading / granulation process described in Example 2 of patent application EP-A-0976408, a composition containing 15.00 g of calcium polystyrene sulfonate resin, 0.25 g of, was prepared per unit dose. sodium carboxymethylcellulose (1900 mPa.s at 2%), 1 g of medium viscosity hydroxypropylcellulose (5000 mPa.s at 2%), 0.02 g of aspartame and 0.01 g of methylcellulose (90 mPa.s).

Comparative Example 3: Preparation of a resin composition with idroxypropyl methylcellulose as a functional excipient

15.00 kg of calcium polystyrene sulphonate resin and 0.25 kg of hydroxypropylmethylcellulose were incorporated into a dump mixer, and direct mixing was carried out at room temperature until a homogeneous composition was obtained.

Comparative Example 4: Preparation of a resin composition with preqelatinized starch as a functional excipient

Following a procedure analogous to that of Comparative Example 3, a composition containing 15.00 kg of calcium polystyrene sulfonate resin and 0.25 kg of pregelatinized starch was prepared.

Comparative Example 5: Preparation of a resin composition without functional excipients Following a procedure analogous to that of Comparative Example 3, a composition free of hydroxypropyl cellulose containing 15.00 kg of calcium polystyrene sulfonate resin was prepared. Example 1: Preparation of the composition

15.00 kg of calcium polystyrene sulfonate resin, 0.25 kg of hydroxypropylmethylcellulose, and 0.25 kg of pregelatinized starch were incorporated into a dump mixer.

It was mixed at room temperature until a homogeneous composition was obtained.

The composition was packaged in sachets containing 15.5 g of composition.

Example 2: Preparation of the composition

Following a procedure analogous to that described in Example 1, a composition containing 15.00 kg of calcium polystyrene sulfonate resin, 0.125 kg of hydroxypropylmethylcellulose, and 0.125 kg of pregelatinized starch was prepared.

The composition was packed in sachets containing 15.25 g of composition.

Example 3: Preparation of the composition

Following a procedure analogous to that described in Example 1, a composition containing 15.00 kg of sodium polystyrene sulfonate resin, 0.25 kg of hydroxypropylmethylcellulose, and 0.25 kg of pregelatinized starch was prepared.

The composition was packaged in sachets containing 15.5 g of composition.

Example 4: Preparation of the composition

Following a procedure analogous to that described in Example 1, a composition containing 15.00 kg of sodium polystyrene sulfonate resin, 0.125 kg of hydroxypropylmethylcellulose, and 0.125 kg of pregelatinized starch was prepared. The composition was packed in sachets containing 15.25 g of composition.

Example 5: Preparation of the composition

Following a procedure analogous to that described in Example 1, a composition containing 15.00 kg of calcium polystyrene sulfonate resin, 0.25 kg of hydroxypropylmethylcellulose, 0.25 kg of pregelatinized starch, 0.1 kg of banana flavor was prepared , 0.02 kg of sucralose and 0.01 kg of Neo-DHC.

The composition was packaged in sachets containing 15.63 g of composition.

Example 6: Determination of the viscosity of resin compositions Aqueous suspensions were prepared from the unit doses of the compositions prepared in Example 1 and in comparative examples 1 and 2 in 100 ml of water. Each unit dose contained 15 g of cation exchange resin.

The viscosity was determined using a Brookfield LVT6 viscometer equipped with spindle n ^e 1 and at a constant speed of 30 rpm.

In Figure 1 it can be seen that the compositions described in the state of the art (Comparative Examples 1 and 2) had a viscosity much higher than that considered suitable for oral administration, and significantly higher than the viscosity of the composition of the invention of Example 1.

The composition of Comparative Example 1 had a viscosity of about 3500 mPa.s, the composition of Comparative Example 2 a viscosity of about 500 mPa.s, while the composition of the invention of Example 1 had a viscosity below or near 100 mPa.s, which is appropriate for oral administration.

Example 7: Determination of the initial viscosity of resin compositions

Aqueous suspensions were prepared from unit doses of the compositions prepared in Example 1 and in Comparative Examples 3 to 5 in a proportion of one unit dose per 100 ml of water. Each unit dose contained 15 g of cation exchange resin.

The suspensions were prepared by pouring the equivalent of five unit doses of the corresponding formulation into a glass containing 500 ml of water. Once prepared the suspensions were kept under stirring at 600 rpm for 2 minutes.

The compositions tested can be included in the 2 ² factorial design of Table I. This table contains the compositions that have been tested, the excipients that compose them and the viscosities of the aqueous suspensions thereof determined at 1 minute after completion. The stirring period at 600 rpm:

TABLE I

The arrangement of the results according to this design allows to easily visualize the synergistic effect of the combination of pregelatinized starch and HPMC. It can be seen that the presence of pregelatinized starch in the formulation has virtually no influence on the viscosity at 1 minute when the formulation does not include HPMC, while exerting a significant effect in the presence of HPMC. This results in a synergistic effect of the combination of pregelatinized starch and HPMC on the viscosity of the suspension in the initial instants and at least up to 15 minutes, and substantially constant up to 40 minutes. The results obtained in this example have been represented in Figure 2.

It can be seen that the composition of the invention prepared in Example 1 has an initial viscosity of approximately 80 mPa.s that remains substantially stable for a period of not less than 15 minutes. The increase in viscosity observed in the case of suspensions prepared from the compositions of comparative examples 4 and 5 does not really correspond to an increase in viscosity, but to the sedimentation of the resin that slows the viscometer spindle .

It is observed that the composition that does not contain any excipient (Comparative Example 5), sediments massively from minute 5.

It is also observed that the composition containing only pregelatinized starch as a functional excipient (Comparative Example 4) is not capable of generating a viscosity sufficient to keep the resin in suspension, so that the behavior of this composition is substantially analogous to that of the composition of Comparative Example 5.

It can be seen that the viscosity recorded for the composition of Comparative Example 3, which contains only hydroxypropyl methylcellulose as an excipient, is significantly lower than that obtained with the composition of the invention.

Example 8: Determination of the resuspension capacity of resin compositions

Aqueous suspensions were prepared from unit doses of the compositions prepared in examples 1 and 2, and in comparative examples 3 to 5 in a proportion of one unit dose per 100 ml of water. Each unit dose contained 15 g of cation exchange resin.

The suspensions were prepared by pouring the equivalent of five unit doses of the corresponding formulation into a glass containing 500 ml of water. Once the suspensions were prepared, they were kept under stirring at 600 rpm for 2 minutes, and then kept at rest for 1 hour.

The viscosity was determined using a Brookfield LVT6 viscometer equipped with spindle n ^e 1 and at a constant speed of 0.3 rpm for suspensions prepared from the compositions of Example 1 and Comparative Example 3, and spindle n ^e 2 for the compositions of Comparative Examples 4 and 5, also using the speed of 0.3 rpm. The use of different spindles is due to the different volumes of precipitates formed according to the composition tested.

By using the speed of 0.3 rpm, the exact point of solid sediment rupture can be determined with greater precision, offering a reference of the force necessary to initiate sediment resuspension, that is, an indication of the force Starter required to start the viscometer spindle.

In the same way as in Example 7, the compositions tested and the results can be included in the 2 ² factorial design with center point shown in Table II. Said table includes the compositions that have been tested, the excipients that compose them and the viscosity of the breaking point for each of the aqueous suspensions:

TABLE II

It can be seen that the combination of pregelatinized starch and HPMC of Examples 1 and 2 leads to a viscosity at the breaking point significantly lower than that observed when only one of the excipients is used. Figure 3 shows the results obtained for the viscosity for each of the compositions tested. The maximum of each one of the curves offers an indication of the force necessary in each case to start the viscometer of the viscometer, which in turn is a reference to the ease of resuspension of the sediment.

This influence is shown to a greater extent if the viscosity at the breaking point is normalized to the same volume of sediment, as shown in Table III. This table includes the height of the tank and the normalized viscosity at the breaking point for each of the compositions tested:

TABLE III

The results in Table III indicate, beyond the variability inherent in the precision of the method, that the combination of pregelatinized starch and HPMC significantly reduces the force necessary to resuspend a sedimented aqueous suspension of a cation exchange resin, in comparison with the use of each of the excipients separately.

The normalized viscosities obtained in this Example 8 for the compositions tested have been represented in Figure 4.

It can be seen that the compositions of the invention prepared in Examples 1 and 2 have a normalized viscosity at the breaking point significantly lower than that obtained in the case of compositions containing only one of the functional excipients or none.

It is observed that the composition that does not contain any functional excipient (Comparative Example 5), has a normalized viscosity at the breaking point approximately equal to 16000 mPa.s / cm.

It can be seen that the normalized viscosity at the breaking point approximately equal to 1 1200 mPa.s / cm recorded for the composition of the Comparative Example 3, which contains only HPMC as a functional excipient.

It is also observed that the composition containing only pregelatinized starch (Comparative Example 4) as a functional excipient has a normalized viscosity at the breaking point of approximately 8900 mPa.s / cm.

Therefore, it follows from this test that the compositions of the invention, comprising the combination of HPMC and pregelatinized starch, have a remarkable resuspension capacity.

Claims

one . - Solid pharmaceutical composition characterized in that it comprises a cation exchange resin, hydroxypropyl methylcellulose and pregelatinized starch.

2. - Composition according to claim 1, characterized in that it further comprises a flavoring agent and, optionally, a sweetening system.

3. - Composition according to claim 1 or 2, characterized in that the resin is selected from the group consisting of calcium polystyrene sulfonate and sodium polystyrene sulfonate.

4. Composition according to claim 3, characterized in that the resin is calcium polystyrene sulfonate.

5. - Composition according to claim 3, characterized in that the resin is sodium polystyrene sulfonate.

6. - Composition according to any of claims 1 to 5, characterized in that the content of cation exchange resin is between 95.0% and 99.8% by weight with respect to the total weight of the composition.

7. - Composition according to any of claims 1 to 6, characterized in that the hydroxypropylmethylcellulose content is comprised between 0.1% and 2.5% by weight with respect to the total weight of the composition.

8. - Composition according to any of claims 1 to 7, characterized in that the pregelatinized starch content is comprised between 0.1% and 2.5% by weight with respect to the total weight of the composition.

9. - Composition according to claim 1, characterized in that it comprises between 95.0% and 97.5% by weight of cation exchange resin, between 1.25% and 2.5% by weight of HPMC, and between 1.25% and 2.5% by weight of pregelatinized starch.

10. - Composition according to claim 2, characterized in that it comprises between 0.1% and 1% by weight of a flavoring agent and between 0.05% and 0.5% by weight of a sweetener system.

eleven . - Composition according to any of claims 1 to 10 for use in the treatment of hyperkalemia.

12. - Use of the composition according to any of claims 1 to 10 to prepare solid forms of a cation exchange resin for oral administration.

13. - Solid form for oral administration characterized in that it comprises a therapeutically effective amount of the composition according to any one of claims 1 to 10.

14. - Solid form according to claim 13, characterized in that they are presented as a unit dose or in a bulk container for unit dosage at the time of administration to the patient.

15. - Solid form according to claim 14, characterized in that the unit dose is contained in a single-dose container.

16. Solid form according to claim 15, characterized in that it comprises an amount of cation exchange resin comprised between 5 g and 20 g, an amount of HPMC comprised between 0.08 g and 0.33 g, and an amount of pregelatinized starch comprised between 0.08 g and 0.33 g.

17. Solid form according to claim 16, characterized in that it comprises 15 g of cation exchange resin, 0.25 g of HPMC and 0.25 g of pregelatinized starch.

18. Solid form according to claim 17, characterized in that it further comprises 0.1 g of flavoring agent, and a combination of 0.02 g of sucralose and 0.01 g of neohesperidine DC as a sweetener system.